Due to concerns over potential immune response and supply shortages associated with autografts and allografts, synthetic bone graft substitutes (SBGSs) for augmenting the bone have rapidly gained popularity in the field of implantation. SBGSs are widely used in implantation due to their biocompatibility, osteoconduction, and minimal risk of disease transmission. Typical ceramic bone graft materials such as hydroxyapatite (HA, Ca10(PO4)6(OH)2), β-tricalcium phosphate (β-TCP, β-Ca3(PO4)2) and calcium sulfate (CS, CaSO4), can be presented in different product forms such as powder, granule, pellet, putty, or block to apply to various bone damage conditions. At present, many fabrication methods for bone grafts have been developed, as summarized in Table 1.
TABLE 1Product name(producer, factory)Composition (content)Comments (phase)Healos (Depuy Spine)SpongeProOsteon (Interpore Int.,Particulate or block brittle.USA) Previous name: ReplamRadiopaore size 190-230 μm)Hydroxyapatite-Porites or500: Porites Gonipora (largeRHAPpores) R: Resorbcity impedesassessment of healing. Slowresorption R-formCollagraft (Zimmer Inc, USA)HA coated 70% Type I bovineGranules and strips requirecollagenaugmentation with aspiratedmarrowMBCP (Biomatlante)Replaniform corallineGranules, rectangular sticks,macroporous HA 200: Poritescylinders or wedges(pableTriosite (Zimmer Europe Ltd,60% HA, 40% TCPAlso called MBCPUK)(macroporous biphasiccalcium phosphate) or BCPBCP (Bioland)60% HA, 40% TCPOstilit (Stryker Howmedica20% HA, 80% TCP, withoutGranules and blocks forOsteonics, UK)macroporousnonstructural graftsBoneSave (Stryker20% HA, 80% TCP,Granules, stronger than Ostilit,Howmedica Osteonics, UK)pore size: 400-600 μmfor use as a void filler and ingraftingCerasorb ORTHO (curasan)Pure phase β-TCP,Granular size being 500-1,000 μmmicropores: <80 μmor 1,000-2,000 μmVitoss ™ Scaffold (curasan)β-TCP, micropores: <1-1000 μmMorsel (1-4 mm sizes) andblocks (9 × 23 mm cylinder)Conduit ™ TCP Granules>99% (β-TCP) Ca3(PO4)2,Irregular shaped granules(DePuy Spine)pore: 1-600 μmhaving an average diameterbetween 1.5 and 3 mmCellplex ™ TCP syntheticPorous calcium phosphatecancellous bone (Wright)made from TCP, pore size:100-400 μmCeros 82β-TCP, porosity varies toLower compressive strengthadjust resorption between 6than Ceros 80and 12 monthsSynthes (USA) chronOS ™β-TCP pore size: 100-500 μmGranules, blocks, wedge and(Synthes)cylindersCalciresorb (Ceraver Osteal,Porous TCPPeriodontal applicationsFrance)Synthograf (Milter, USA)Small size and dense TCPPeriodontal applicationsAugmen (Milter, USA)Large size and dense TCPPeriodontal applicationsSkelite ™ (MilleniumMultiphase, porous calciumGranules and blocksBiologix)phosphateNorian Skeletal Repair SystemSelf-setting calcium phosphateInjectable cement,(SRS)cementaugmentation of fracture
There is great demand in the field of implementation surgery for an ideal SBGS. The in vivo resorption rate is one vital property of SBGSs that can be improved. SBGSs for implants should be rapidly resorbable and replaced by new bone so that implants can be placed as early as possible in the augmented site. However, the ideal resorption period for SBGS use in implants (especially in dentistry) is still uncertain. Clinical studies have reported that a stress-free healing period of 3-6 months is prerequisite to implant osseointegration. For example, a 3-6-month healing period was proposed by Kawai et al. in their radiographic studies of healing of jawbone defects and fractures (Kawai T, Murakami S, Hiranuma H, Sakuda M. Healing after removal of benign cysts and tumors of the jaws. A radiologic appraisal. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1995; 79(4): 517-25; Kawai T, Murakami S, Hiranuma H, Sakuda M. Radiographic changes during bone healing after mandibular fractures. Br J Oral Maxillofac Surg 1997; 35(5): 312-8). It was suggested that at a natural healing rate, most jawbone defects required an average time of 3-6 months to heal.
Calcium sulfate (CS) is a rapidly resorbable and biocompatible bone substitute with a bone regeneration effect and angiogenic effect. Depending on the amount of crystal water, calcium sulfate can be classified as calcium sulfate dihydrate (CaSO4.2H2O, i.e., gypsum), calcium sulfate hemihydrate (CaSO4.0.5H2O, i.e., plaster of Paris) or calcium sulfate anhydrite (CaSO4). The following are the chemical reaction formulae of the above reactions:Dehydration: CaSO4.2H2O(s)+heat→CaSO4.½H2O(s)+1½H2OCaSO4.½H2O(s)+heat→CaSO4+2H2OHydration: CaSO4.½H2O(s)+3/2H2O→CaSO4.2H2O(s)The in vivo resorption period of calcium sulfate hemihydrate is longer than that of calcium sulfate dihydrate. However, calcium sulfate hemihydrate will transform into calcium sulfate dihydrate through hydration. Therefore, in commercial processes for producing tablet calcium sulfate bone substitute, water is added to calcium sulfate hemihydrate to form tablet calcium sulfate dihydrate and then the tablet calcium sulfate dihydrate is transformed into calcium sulfate hemihydrate by dehydration. CS is associated with many other biomaterials. In vitro studies of the attachment of osteoblast cells to CS and the resorption of CS by osteoclasts have been reported. However the high in vivo resorption rate of CS of 1-2 months is considered too rapid, as it can limit bone regeneration and cause serous drainage in some clinical applications.
It has been recommended that merging CS with a less-resorbable calcium phosphate compound would be better for human applications. Many studies have worked on combining CS with other calcium phosphates like HAp, β-tricalcium phosphate (β-TCP), and α-tricalcium phosphate (α-TCP) (Urban R M, Turner T M, Hall D J, Inoue N, Gitelis S. Increased bone formation using calcium sulfate-calcium phosphate composite graft. Clin Orthop Mat Res 2007; 459:110-7; Nilsson M, Wang J S, Wielanek L, Tanner K E, Lidgren L. Biodegradation and biocompatability of a calcium sulphate-hydroxyapatite bone substitute. J Bone Joint Surg 2004; 86(1):120-125). US Publication No. 20050119746 provides an artificial bone mineral substitute material comprising at least one ceramic and at least one water soluble non-ionic X-ray contrast agent and illustrates an embodiment comprising 1-30% calcium sulfate hemihydrate and 50-99% α-TCP. However, their resorption rates were far too slow.
Amorphous calcium phosphate (ACP; with an approximate compositional formula of Ca3(PO4)2.0.8H2O) is a non-crystalline and the most soluble form of tricalcium phosphate. It is usually treated in vivo as a precursor of biological bone apatite during bone formation. In vitro, ACP is the first phase that precipitates from a supersaturated solution prepared by rapidly mixing solutions containing calcium and phosphate ions. The composition and poor crystalline structure of ACP mimic natural bone apatite, and would be a better bone substitute than highly crystalline hydroxyapatite (HAp). Previous studies confirmed that ACP shows better bioactivity than HAp, because greater adhesion, proliferation, and differentiation of osteogenic cells were observed on ACP substrates than crystalline HAp substrates. However, ACP will transform to Hap with longer resorption rate after contacting water through phase transformation.
U.S. Pat. No. 7,351,280 relates to a composition and method for producing interconnective macroporous, resorbable and injectable calcium phosphate-based cements (MICPCs), which provide a self-setting calcium phosphate cement (CPC). The invention of the patent adds carbonate, magnesium, zinc, fluoride and pyrophosphate ions to stabilize ACP. U.S. Pat. No. 7,670,419 discloses a hydraulic cement based on calcium phosphate for surgical use comprising A) a first component comprising powder particles of calcium phosphate; and B) a second component comprising water. The invention of the patent uses ACP that is preheated to 500° C. and then milled to shorten time of hydrating and hardening CPC. US Publication No. 20020183417 relates to a calcium phosphate bone graft material, to a process for making the calcium phosphate bone graft material, and to an osteoimplant fabricated from the calcium phosphate bone graft material. The invention uses plasma spray to coat ACP on the surface of Hap to form a new bone substitute. US Publication No. 20080014242 discloses a synthetic bone substitute material suitable for use as a replacement for cancellous bone in a bone graft composition, the material comprising a reticulated framework of interconnecting bioceramic struts defining an interconnecting interstitial void volume, and a solid non-porous composition substantially filling the interstitial void volume and in intimate contact with the reticulated framework, the pore-filling composition comprising calcium sulfate. However, the bone substitutes provided in the above prior art cannot provide satisfactory resorption rate.
Therefore, there remains a need in the art for improved bone substitute materials providing resorption rate suitably parallel to the natural healing rate of the human bone.